U.S. patent number 11,168,058 [Application Number 16/491,642] was granted by the patent office on 2021-11-09 for manufacture of a crystalline pharmaceutical product.
This patent grant is currently assigned to ORION CORPORATION. The grantee listed for this patent is ORION CORPORATION. Invention is credited to Merja Reunanen, Anna Staffans.
United States Patent |
11,168,058 |
Reunanen , et al. |
November 9, 2021 |
Manufacture of a crystalline pharmaceutical product
Abstract
The present disclosure relates to crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having specific surface
area (SSA) in the range from about 8 to about 16 m.sup.2/g,
preferably from about 10 to about 15 m.sup.2/g, and to the method
for the preparation of such particles. Compound (I) is a potent
androgen receptor (AR) modulator which is useful as a medicament
for example in the treatment of prostate cancer.
Inventors: |
Reunanen; Merja (Espoo,
FI), Staffans; Anna (Espoo, FI) |
Applicant: |
Name |
City |
State |
Country |
Type |
ORION CORPORATION |
Espoo |
N/A |
FI |
|
|
Assignee: |
ORION CORPORATION (Espoo,
FI)
|
Family
ID: |
61599196 |
Appl.
No.: |
16/491,642 |
Filed: |
February 27, 2018 |
PCT
Filed: |
February 27, 2018 |
PCT No.: |
PCT/FI2018/050143 |
371(c)(1),(2),(4) Date: |
September 06, 2019 |
PCT
Pub. No.: |
WO2018/162793 |
PCT
Pub. Date: |
September 13, 2018 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20200039940 A1 |
Feb 6, 2020 |
|
Foreign Application Priority Data
|
|
|
|
|
Mar 7, 2017 [FI] |
|
|
20175202 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
35/00 (20180101); C07D 231/14 (20130101); A61K
45/06 (20130101) |
Current International
Class: |
C07D
231/14 (20060101); A61K 45/06 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
8921378 |
December 2014 |
Tormakangas et al. |
8975254 |
March 2015 |
Wohlfahrt et al. |
|
Foreign Patent Documents
|
|
|
|
|
|
|
WO 2012/143599 |
|
Oct 2012 |
|
WO |
|
WO 2016/120530 |
|
Aug 2016 |
|
WO |
|
Other References
Caira, Crystalline Polymorphism of Organic Compounds, Topics in
Current Chemistry, 1999, vol. 198, p. 164-208. (Year: 1999). cited
by examiner .
International Search Report, issued by the European Patent Office
in International Application No. PCT/2018/050143, dated Apr. 20,
2018 (2 pages). cited by applicant .
Annex 1. Comparative crystallization experiments between particles
of the invention and particles of D1 (WO 2016/120530) (1 page).
cited by applicant .
Third Party Observation for Application No. EP20180709661 dated
Mar. 12, 2021 (4 pages). cited by applicant.
|
Primary Examiner: Cheng; Karen
Attorney, Agent or Firm: Finnegan, Henderson, Farabow,
Garrett & Dunner, LLP
Claims
The invention claimed is:
1. Crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-
-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a specific
surface area (SSA) in a range from about 8 to about 16
m.sup.2/g.
2. The crystalline particles according to claim 1 having a volume
median diameter (Dv50).gtoreq.10 .mu.m.
3. The crystalline particles according to claim 1 having a volume
median diameter (Dv50) ranging from between 10 .mu.m and 1000
.mu.m.
4. The crystalline particles according to claim 1 having a volume
median diameter (Dv50) ranging from between 100 .mu.m and 1000
.mu.m.
5. The crystalline particles according to claim 4, wherein the
particles have a rounded particle shape.
6. The crystalline particles according to claim 5 characterized by
a mean aspect ratio higher than 0.8, and/or a mean high sensitivity
(HS) circularity higher than 0.89.
7. The crystalline particles according to claim 6 characterized by
a mean aspect ratio higher than 0.8 and a mean high sensitivity
(HS) circularity higher than 0.89.
8. The crystalline particles according to claim 7 characterized by
a mean aspect ratio higher than 0.82 and a mean high sensitivity
(HS) circularity higher than 0.9.
9. The crystalline particles according to claim 1 having a volume
median diameter (Dv50) ranging from between 10 .mu.m and 100
.mu.m.
10. Crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having a rounded
particle shape and a volume median diameter (Dv50) ranging from
between 100 .mu.m and 1000 .mu.m.
11. A pharmaceutical dosage form comprising
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) as an active
ingredient, wherein the active ingredient is in the form of the
crystalline particles according to claim 1.
12. A pharmaceutical dosage form comprising
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) as an active
ingredient, wherein the active ingredient is prepared from the
crystalline particles according to claim 10.
13. The pharmaceutical dosage form according to claim 12, wherein
the crystalline particles are milled to provide a volume median
diameter (Dv50) ranging from between 10 .mu.m and 100 .mu.m.
14. The crystalline particles according to claim 1, wherein the
specific surface area (SSA) is analyzed using a three-point
nitrogen adsorption technique based on the Brunauer, Emmett and
Teller (BET) theory.
15. The crystalline particles according to claim 6, wherein the
mean aspect ratio and/or mean high sensitivity (HS) circularity is
determined by an optical microscopy method on a dry powder
dispersion.
16. The crystalline particles according to claim 2, wherein the
volume median diameter (Dv50) is measured by laser light
diffraction using air as dispersion medium and applying Fraunhofer
optical model.
17. A method for preparing crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxy-ethyl)-1H-pyrazole-3-carboxamide (I) according to claim 1:
a) providing
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-
-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) in a solvent
which comprises ethanol and water, wherein the amount of water is
35-60%, per weight of the solvent; b) heating the mixture to about
refluxing temperature until
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) has dissolved; c)
cooling the mixture to about 20-35.degree. C. during at least 3
hours, optionally with seeding; d) adding, optionally
simultaneously with step c), water during at least 1 hour, such
that after step d) the amount of water in the solvent is 55-80% per
weight of said solvent; and e) isolating the precipitate.
18. The method according to claim 17, wherein the particles have a
volume median diameter (Dv50) ranging from between 100 .mu.m and
1000 .mu.m.
19. The method according to claim 17, wherein the particles have a
rounded particle shape.
20. The method according to claim 17, wherein the particles have a
specific surface area (SSA) in a range from about 8 to about 16
m.sup.2/g.
21. The method according to claim 17, wherein in step a) the
solvent consists essentially of ethanol and water.
22. The method according to claim 21, wherein in step a) the
solvent contains 35-60% of water and 40-65% of ethanol per weight
of the solvent.
23. The method according to claim 17, wherein in step d) the
temperature of the mixture is kept within about 20-35.degree. C.
during the addition of water.
24. The method according to claim 17, wherein steps c) and d) are
carried out simultaneously.
25. The method according to claim 17, wherein after step d) the
mixture is cooled further to about 10-30.degree. C. for at least 1
hour.
26. The method according to claim 17, wherein during step c) the
mixture is seeded at about 50-70.degree. C.
27. The method according to claim 17, wherein the amount of
compound (I) in step a) is about 1-20% per weight of the
solvent.
28. The method according to claim 17, wherein the isolated
precipitate is dried under reduced pressure at a temperature of at
least 30.degree. C.
29. The method according to claim 28, wherein the isolated
precipitate is dried under reduced pressure at 40-60.degree. C.
Description
This is a National Stage Application under 35 U.S.C. .sctn. 371 of
International Patent Application No. PCT/FI2018/050143, filed Feb.
27, 2018, which claims the benefit of Finnish Patent Application
No. 20175202, filed Mar. 7, 2017, both of which are incorporated
herein by reference.
FIELD OF THE INVENTION
The present invention relates to crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having specific surface
area (SSA) in the range from about 8 to about 16 m.sup.2/g,
preferably from about 10 to about 15 m.sup.2/g, and to the method
for the preparation of such particles.
BACKGROUND OF THE INVENTION
The compound
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) and manufacture thereof
have been disclosed in WO 2011/051540. Compound (I) is a potent
androgen receptor (AR) modulator useful in the treatment of cancer,
particularly AR dependent cancer such as prostate cancer, and other
diseases where AR antagonism is desired. Compound (I) is
represented by the structure:
##STR00001##
As the hydrogen atom of the pyrazole ring may exist in tautomeric
equilibrium between the 1- and 2-position, it is recognized by the
skilled person that the above structure and the chemical name
"N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-
-hydroxyethyl)-1H-pyrazole-3-carboxamide (I)," as referred to
herein, is inclusive of the tautomer of compound (I), namely
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-3-(1--
hydroxyethyl)-1H-pyrazole-5-carboxamide.
Compound (I) is poorly soluble in water. Poorly soluble compounds
often suffer from low oral bioavailability. Enhancement of
bioavailability of poorly soluble drugs is routinely attempted by
micronization. Micronization, i.e. reduction of particle size to
the range of only few micrometers, typically increases the
dissolution rate of the poorly soluble drug through increased
specific surface area (SSA). Micronized particles, however, often
suffer from poor flow and dispersion properties causing drawbacks
in subsequent pharmaceutical processing.
A stable crystalline form of compound (I) and a method for the
preparation thereof by crystallization from a mixture of
acetonitrile and water has been disclosed in WO 2016/120530. The
method produces small irregular particles with sharp edges. Such
particles are not optimal for pharmaceutical processing purposes
either, for example due to poor flowability of the powder or
cumbersome isolation. Therefore, there is a need for crystalline
particles of compound (I) which are better suited for
pharmaceutical processing.
SUMMARY OF THE INVENTION
It has now been found that compound (I) can be obtained from the
crystallization solvent as crystalline particles which have better
properties for subsequent pharmaceutical processing. In one aspect,
the obtained particles have consistent and relatively high specific
surface area (SSA) in the range of 8-16 m.sup.2/g, preferably in
the range of 10-15 m.sup.2/g, large volume median diameter, for
example in the range of 100-1000 .mu.m, and narrow particle size
distribution. In another aspect, the particles have rounded
particle shape. The particles having rounded particle shape are
characterized by substantial lack of sharp edges. The particles of
the present invention are easy to isolate, free flowing and exhibit
reduced stickiness. Moreover, it was found that the specific
surface area (SSA) of the particles in the range of from about 8 to
about 16 m.sup.2/g, preferably from about 10 to about 15 m.sup.2/g,
does not significantly change even though the volume median
diameter of the particles is reduced to the range of 10-100 .mu.m,
e.g. by milling. This ascertains consistent bioavailability
regardless of the variability in particle size.
Therefore the particles according to the present invention are
particularly well suited for pharmaceutical processing.
Thus, according to one aspect, the present invention provides
crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxy-ethyl)-1H-pyrazole-3-carboxamide (I) having specific
surface area (SSA) in the range from about 8 to about 16 m.sup.2/g,
preferably from about 10 to about 15 m.sup.2/g.
According to another aspect, the present invention provides
crystalline particles of
N-((5)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-h-
ydroxy-ethyl)-1H-pyrazole-3-carboxamide (I) having specific surface
area (SSA) in the range from about 8 to about 16 m.sup.2/g,
preferably from about 10 to about 15 m.sup.2/g, and a volume median
diameter (Dv50).gtoreq.10 .mu.m, preferably .gtoreq.15 .mu.m, more
preferably .gtoreq.20 .mu.m.
According to another aspect, the present invention provides
crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxy-ethyl)-1H-pyrazole-3-carboxamide (I) having specific
surface area (SSA) in the range from about 8 to about 16 m.sup.2/g,
preferably from about 10 to about 15 m.sup.2/g, and a volume median
diameter (Dv50) between 10-1000 .mu.m, preferably between 15-800
.mu.m, more preferably between 20-750 .mu.m.
According to another aspect, the present invention provides
crystalline particles of
N-((5)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-h-
ydroxy-ethyl)-1H-pyrazole-3-carboxamide (I) having specific surface
area (SSA) in the range from about 8 to about 16 m.sup.2/g,
preferably from about 10 to about 15 m.sup.2/g, and a volume median
diameter (Dv50) between 100-1000 .mu.m, preferably between 120-800
.mu.m, more preferably between 150-750 .mu.m. According to one
particular aspect of the above embodiment of the invention, the
crystalline particles have rounded particle shape.
According to still another aspect, the present invention provides
crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having volume median
diameter (Dv50) between 100-1000 .mu.m, preferably between 120-800
.mu.m, more preferably between 150-750 .mu.m, and rounded particle
shape.
According to still another aspect, the present invention provides a
pharmaceutical dosage form comprising
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) as an active
ingredient, wherein the active ingredient is in the form of
crystalline particles according to any of the above
embodiments.
According to still another aspect, the present invention provides a
pharmaceutical dosage form, wherein the active ingredient is
prepared from crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxy-ethyl)-1H-pyrazole-3-carboxamide (I) having volume median
diameter (Dv50) between 100-1000 .mu.m and rounded particle shape,
for example by milling said particles to provide volume median
diameter (Dv50) between 10-100 .mu.m.
According to still another aspect, the present invention provides a
pharmaceutical dosage form, wherein the active ingredient is
prepared from crystalline particles of
N-((5)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-h-
ydroxy-ethyl)-1H-pyrazole-3-carboxamide (I) having specific surface
area (SSA) in the range from about 8 to about 16 m.sup.2/g,
preferably from about 10 to about 15 m.sup.2/g, volume median
diameter (Dv50) between 100-1000 .mu.m and rounded particle shape,
for example by milling said particles to provide volume median
diameter (Dv50) between 10-100 .mu.m.
According to still another aspect, the present invention provides a
method for preparing crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I), the method comprising
the steps of a) providing
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) in a solvent which
comprises ethanol and water, wherein the amount of water is 35-60%,
preferably 40-58%, more preferably 42-55%, per weight of the
solvent; b) heating the mixture to about refluxing temperature
until
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) has dissolved; c)
cooling the mixture to about 20-35.degree. C. during at least 3
hours, preferably during about 4 to about 8 hours, optionally with
seeding; d) adding, optionally simultaneously with step c), water
during at least 1 hour, preferably during about 2 to about 10
hours, such that after step d) the amount of water in the solvent
is 55-80%, preferably 58-78%, more preferably 60-75%, per weight of
said solvent; and e) isolating the precipitate.
According to still another aspect, the present invention provides
crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) having volume median
diameter (Dv50) between 100-1000 .mu.m, preferably between 120-800
.mu.m, more preferably between 150-750 .mu.m, and having rounded
particle shape, said particles being obtainable by a method
comprising the steps of a) providing
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-
-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide (I) in a solvent
which comprises ethanol and water, wherein the amount of water is
35-60%, preferably 40-58%, more preferably 42-55%, per weight of
the solvent; b) heating the mixture to about refluxing temperature
until
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) has dissolved; c)
cooling the mixture to about 20-35.degree. C. during at least 3
hours, preferably during about 4 to about 8 hours, optionally with
seeding; d) adding, optionally simultaneously with step c), water
during at least 1 hour, preferably during about 2 to about 10
hours, such that after step d) the amount of water in the solvent
is 55-80%, preferably 58-78%, more preferably 60-75%, per weight of
said solvent; and e) isolating the precipitate.
According to one particular embodiment, particles being obtainable
by the above method have specific surface area (SSA) in the range
from about 8 to about 16 m.sup.2/g, preferably from about 10 to
about 15 m.sup.2/g.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows particle size distribution of crystalline particles of
compound (I) prepared according to the present invention as
analyzed by laser light diffraction.
FIG. 2 shows a scanning electron microscope image (50 fold
magnification, bar 500 .mu.m) of crystalline particles of compound
(I) prepared according to the present invention.
FIG. 3 (reference) shows a scanning electron microscope image (500
fold magnification) of particles of compound (I) prepared according
to Example 1 of WO 2016/120530.
DETAILED DESCRIPTION OF THE INVENTION
The term "particles having rounded particle shape", as used herein,
refers to particles according to the present invention having
substantially spherical, elliptical or potato-like geometries with
curved surfaces substantially lacking sharp or rough edges, such
geometries and surfaces being consistent and apparent when the
particles are examined under a scanning electron microscope,
particularly with 50-100 fold magnification. The rounded particles
according to the invention are further characterized by having mean
aspect ratio higher than 0.8, preferably higher than 0.82 and/or
mean HS (high sensitivity) circularity higher than 0.89, preferably
higher than 0.9.
The term "aspect ratio", as used herein, refers to the ratio of the
shortest dimension to the longest dimension of a particle and is in
the range of 0 to 1.
The term "high sensitivity (HS) circularity", as used herein,
refers to a parameter which is equal to the square of the
circularity where the circularity is equal to the ratio of the
circumference of a circle equal to the particle's projected area to
the actual circumference (perimeter) of a particle. Thus, high
sensitivity (HS) circularity is calculated as
(4.pi..times.Area)/(Perimeter.sup.2).
The mean aspect ratio and mean high sensitivity (HS) circularity of
the particles can be determined by an optical microscopy based
method on a dry dispersion, such as Morphologi G3.TM. particle size
and particle shape analyser (Malvern Instruments). The sample can
be prepared by using the Morphologi G3.TM. integrated dry powder
disperser (Malvern Instruments), for example using sample amount of
7 mm.sup.3 and dispersion pressure of 1.0 bar. The automated image
analysis is suitably performed without filters. The applied
magnification depends on the particle size of the analysed powder
being typically 10.times..
The term "crystalline particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I)", as used herein,
refers to particles of compound (I) wherein compound (I) is at
least partly in crystalline, including microcrystalline, form. For
example, the term includes particles of compound (I) wherein
compound (I) is at least partly in the crystalline form I,
disclosed in WO 2016/120530. The X-ray powder diffraction (XRPD)
pattern of crystalline form I has characteristic peaks at about
8.5, 10.4, 16.6, 16.9, and 24.3 degrees 2-theta. Accordingly, the
term includes particles which show XRPD characteristic peaks at
about 8.5, 10.4, 16.6, 16.9, and 24.3 degrees 2-theta.
The particle size distribution of crystalline particles of compound
(I) can be analyzed by laser light diffraction, for example using
Beckman Coulter LS13320 laser diffraction particle size analyzer
equipped with Tornado Dry Powder System using air as dispersion
medium with measurement pressure 24''H.sub.2O.+-.2''H.sub.2O,
sample amount 10 ml, system controlled target 5% for obscuration
and applying Fraunhofer optical model.
The parameters considered are the volumetric diameters in .mu.m of
the 10.sup.th, 50.sup.th and 90.sup.th percentiles of the
particles, expressed as Dv10, Dv50 and Dv90 respectively, which are
determined by assuming that the particles have a geometric shape
equivalent to a sphere.
The specific surface area (SSA) of crystalline particles of
compound (I) can be analyzed using the three-point nitrogen
adsorption technique based on the Brunauer, Emmett and Teller (BET)
theory, for example using TriStar 3000 automated gas adsorption
analyzer, (Micromeritics, Inc.). The samples are suitably vacuum
dried for 20 hours at 40.degree. C. The volumetric method can be
used at the relative pressure range of 0.1-0.3 P/P.sub.0.
The present invention provides a method for preparing crystalline
particles of
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I), the method comprising
the steps of a) providing
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) in a solvent which
comprises ethanol and water, wherein the amount of water is 35-60%,
preferably 40-58%, more preferably 42-55%, per weight of the
solvent; b) heating the mixture to about refluxing temperature
until
N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I) has dissolved; c)
cooling the mixture to about 20-35.degree. C. during at least 3
hours, preferably during about 4 to about 8 hours, optionally with
seeding; d) adding, optionally simultaneously with step c), water
during at least 1 hour, preferably during about 2 to about 10
hours, such that after step d) the amount of water in the solvent
is 55-80%, preferably 58-78%, more preferably 60-75%, per weight of
said solvent; and e) isolating the precipitate.
The solvent to be used in step a) generally comprises ethanol and
water. The amount of water in the solvent of step a) is about
35-60%, preferably 40-58%, more preferably 42-55%, per weight of
the solvent. Preferably, the solvent consists essentially of
ethanol and water. For example, the solvent of step a) contains
35-60% of water and 40-65% of ethanol, preferably 40-58% of water
and 42-60% of ethanol, more preferably 42-55% of water and 45-58%
of ethanol, per weight of the solvent. According to one embodiment,
the solvent of step a) contains 45-52% of water and 48-55% of
ethanol, per weight of the solvent. According to another
embodiment, the solvent of step a) contains 48-55% of water and
45-52% of ethanol, per weight of the solvent.
The amount of compound (I) used in step a) is suitably about 1-20%,
preferably about 5-15%, for example 6-12%, per weight of the
solvent. For example, 150-250 kg of compound (I) is provided in
1500-3800 kg of ethanol-water solvent in a suitable reactor. The
mixture is then heated with stirring, suitably to about refluxing
temperature, for example to about 65-85.degree. C., until compound
(I) has been dissolved. In step c) the mixture is then cooled
slowly to 20-35.degree. C. while stirring mildly, typically with
stirring speed less than 80 rpm. The cooling is carried out during
at least 3 hours, preferably during about 4 to about 8 hours,
optionally with seeding using crystals of compound (I). The seeding
is suitably carried out at a temperature starting from about
75.degree. C. and optionally again at lower temperatures. For
example, the seeding can be carried out once or several times when
the temperature of the mixture is about 50-70.degree. C. The amount
of seeding crystals is typically less than 0.5% per weight of the
compound (I) initially provided to the reactor. The seeding
crystals of compound (I) can be prepared, for example, using the
method described in WO 2016/120530.
In step d) more water is added slowly to the mixture such that
after the water addition the amount of water in the solvent is
55-80%, preferably 58-78%, more preferably 60-75%, per weight of
the solvent. Preferably, the solvent consists essentially of
ethanol and water. For example, the solvent after step d) contains
55-80% of water and 20-45% of ethanol, preferably 58-78% of water
and 22-42% of ethanol, more preferably 60-75% of water and 25-40%
of ethanol, per weight of the solvent.
According to one embodiment, the solvent after step d) contains
60-65% of water and 35-40% of ethanol, per weight of the solvent.
According to another embodiment, the solvent after step d) contains
65-70% of water and 30-35% of ethanol, per weight of the solvent.
According to still another embodiment, the solvent after step d)
contains 70-75% of water and 25-30% of ethanol, per weight of the
solvent.
According to another embodiment, the solvent of step a) contains
48-55% of water and 45-52% of ethanol, per weight of the solvent,
and after step d) 60-65% of water and 35-40% of ethanol, per weight
of the solvent. According to another embodiment, the solvent of
step a) contains 45-52% of water and 48-55% of ethanol, per weight
of the solvent, and in step d) 70-75% of water and 25-30% of
ethanol, per weight of the solvent.
The addition of water is carried out during at least 1 hour,
preferably during about 2 to about 10 hours, for example during
about 6 to about 10 hours. The mixture is stirred mildly during
water addition, typically with stirring speed less than 80 rpm. The
temperature of the mixture is suitably kept within about
20-35.degree. C. during the addition of water.
Alternatively, steps c) and d) can be carried out simultaneously.
In this embodiment water is added during the cooling step. The
procedure of water addition can be carried out as explained above
while cooling the mixture to about 20-35.degree. C. including the
optional seeding. The simultaneous cooling and water addition is
suitably carried out during at least 3 hours, preferably during
4-10 hours.
After step d) the mixture can be cooled further, preferably to
about 10-30.degree. C., for example to 10-20.degree. C., during at
least 1 hour, for example during 1-3 h. After the cooling the
mixture is suitably stirred until the precipitation is complete.
The precipitated crystalline particles are easy to isolate, for
example by centrifuging followed by washing with water and/or
ethanol. The isolated precipitate can be dried under reduced
pressure, for example at vacuum, at a temperature which is at least
30.degree. C., for example 40-60.degree. C., for a period needed to
complete the drying.
The particles obtained by the above method are crystalline, have
typically rounded particle shape and exhibit specific surface area
(SSA) typically in the range from about 8 to about 16 m.sup.2/g,
more typically from about 10 to about 15 m.sup.2/g. The particles
obtained have generally volume median diameter (Dv50) between
100-1000 .mu.m, preferably between 120-800 .mu.m, more preferably
between 150-750 .mu.m, in particular between 180-700 .mu.m, for
example between 200-650 .mu.m. Dv10 is generally greater than about
50 .mu.m, preferably greater than about 60 .mu.m, more preferably
greater than about 70 .mu.m, in particular between 80-500 .mu.m,
for example between 100-400 .mu.m. Dv90 is generally lower than
2000 .mu.m, preferably lower than 1500 .mu.m, more preferably lower
than 1400 .mu.m, in particular between 300-1300 .mu.m, for example
between 400-1200 .mu.m.
Moreover, 80 vol-% of the particles is generally between 50-2000
.mu.m, preferably between 60-1500 .mu.m, more preferably between
70-1400 .mu.m, in particular between 80-1300 .mu.m, for example
between 100-1200 .mu.m.
The rounded particles obtained by the above method are typically
characterized by mean aspect ratio higher than 0.8 and/or mean high
sensitivity (HS) circularity higher than 0.89. More typically, the
rounded particles are characterized by mean aspect ratio higher
than 0.8 and mean high sensitivity (HS) circularity higher than
0.89. Still more typically, the rounded particles are characterized
by mean aspect ratio higher than 0.82 and mean high sensitivity
(HS) circularity higher than 0.9.
As the particles obtained by the above method have large volume
median diameter, narrow particle size distribution and rounded
particle shape characterized by substantial lack of sharp edges,
they are easy to isolate, free flowing and exhibit reduced
stickiness. The specific surface area (SSA) of the rounded
particles obtained by the above method is in the range from about 8
to about 16 m.sup.2/g, preferably from about 10 to about 15
m.sup.2/g, and does not significantly change even though the volume
median diameter (Dv50) of the particles is reduced, for example, to
the range of 10-100 .mu.m by milling or other suitable means. This
ascertains consistent bioavailability regardless of the variability
in particle size. Therefore, if higher homogenity of the tableting
mass if desired, the rounded particles can be milled to the
particle size having Dv50, for example, in the range of 10-100
.mu.m, preferably between 15-95 .mu.m, typically between 20-90
.mu.m, such particles being well suited in the preparation
pharmaceutical dosage forms for oral administration such as
tablets.
The crystalline rounded particles of compound (I) obtained by the
method of the invention can therefore be used as such or in milled
form in the preparation of pharmaceutical dosage forms, such as
tablets, capsules or powders together with excipients which are
known in the art.
The invention is further illustrated by the following examples.
Example 1. Preparation of Crystalline Particles of
N--((S)-1-(3-(3-Chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I)
Granular sodium borohydride (15 kg) and EtOH (1370 kg) were placed
into the 6.3 m.sup.3 enamel reaction vessel. The mixture was
solubilized by stirring for 30 min at 22.degree. C.
(S)-3-acetyl-N-(1-(3-(3-chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-y-
l)-1H-pyrazole-5-carboxamide (225 kg) was added to the reaction
vessel. The mixture was then stirred at 22.degree. C. for 4 hours
to complete the reaction. Then pH of the mixture was adjusted to
acidic with HCl in water. Water (800 kg) was then added and the pH
of the mixture was set to 7.0.+-.1.0 by addition of NaOH in water.
The mixture was warmed to 65.degree. C. and then transferred to 6.3
m.sup.3 jacketed steel reaction vessel. The mixture was warmed to
78.degree. C. to dissolve the mixture. The solution was cooled to
64.degree. C. under nitrogen atmosphere. The solution was seeded at
64.degree. C. under mild stirring. The solution was then cooled
during 8 h to 30.degree. C. under mild stirring. Thereafter water
(2600 kg) was added during 7-10 h at 30.degree. C. under mild
stirring. The mixture was cooled during 2 h to 20.degree. C. under
mild stirring and then stirred further for 1 h. The precipitated
product was isolated by centrifuge, washed with water and dried
under vacuum at 40-60.degree. C. to obtain 214 kg of crystalline
particles with rounded particle shape.
Example 2. Preparation of Crystalline Particles of
N--((S)-1-(3-(3-Chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I)
Water (450 kg), EtOH (920 kg) and
(N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1--
hydroxyethyl)-1H-pyrazole-5-carboxamide (215 kg) were placed into
the 6.3 m.sup.3 steel reaction vessel with 100 kg of rinse EtOH.
The mixture was dissolved by warming to 75.degree. C. Activated
carbon SX Ultra (11 kg) and Celite (21 kg) were added followed by
stirring at 78.degree. C. for 1 h. The mixture was cooled to
75.degree. C. under nitrogen atmosphere and filtered. The filtrate
was transferred into 6.3 m.sup.3 jacketed steel reaction vessel.
The carbonlcelite cake was washed with a warmed (75.degree. C.)
mixture of water (970 kg) and EtOH (345 kg). The washing liquid was
also added to the reaction vessel. The solution was stirred at
78.degree. C. for 30 min and then cooled to 70.degree. C. Mild
stirring was maintained during the rest of the process. The
solution was seeded at 70.degree. C. and then cooled during 4 h to
30.+-.5.degree. C. Thereafter water (840 kg) was added during 6 h
at 30.+-.5.degree. C. The mixture was cooled during 2 h to
20.degree. C. and then stirred further for 1 h. The precipitated
product was isolated by centrifuge, washed with EtOH and dried
under vacuum at 40-60.degree. C. to obtain 190 kg of crystalline
particles with rounded particle shape.
Example 3. Preparation of Crystalline Particles of
N--((S)-1-(3-(3-Chloro-4-cyano-phenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(1--
hydroxyethyl)-1H-pyrazole-3-carboxamide (I)
Water (1400 kg), EtOH (1215 kg) and
(N--((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-3-(1--
hydroxyethyl)-1H-pyrazole-5-carboxamide (210 kg) were placed into
the 6.3 m.sup.3 steel reaction vessel. The mixture was dissolved by
warming to 75.degree. C. Activated carbon SX Ultra (11 kg) and
Celite (21 kg) were added followed by stirring for 1 h. The mixture
was then filtered as hot. The filtrate was transferred into 6.3
m.sup.3 jacketed steel reaction vessel. The carbonlcelite cake was
washed with EtOH (170 kg). The washing liquid was also added to the
reaction vessel. Temperature was adjusted to 70.degree. C. The
solution was seeded at 70.degree. C. and then cooled to 60.degree.
C. Then the mixture was cooled to 30.degree. C. in 4 hours and
water (1050 kg) was added simultaneously. The mixture was stirred
further for 30 minutes. The precipitated product was isolated by
centrifuge, washed with water and dried under vacuum at 70.degree.
C. to obtain 190 kg of crystalline particles with rounded particle
shape.
Example 4. Determination of Particle Size Distribution
The particle size distribution of the crystalline rounded particles
of compound (I) prepared according to the present invention was
determined by laser light diffraction. The determination was
carried out by using Beckman Coulter LS13320 laser diffraction
particle size analyzer equipped with Tornado Dry Powder System
using air as dispersion medium with measurement pressure
24''H.sub.2O.+-.2''H.sub.2O, sample amount 10 ml, system controlled
target 5% for obscuration and applying Fraunhofer optical model.
The results of the particle size analysis are shown in FIG. 1.
According to the analysis, Dv10 value of the particles is 359
.mu.m, Dv50 is 632 .mu.m and Dv90 is 925 .mu.m.
Example 5. Characterization of Particles by Scanning Electron
Microscope (SEM) Images
Crystalline rounded particles of compound (I) prepared according to
the present invention were characterized by scanning electron
microscope imaging. The SEM figure is shown in FIG. 2 (50 fold
magnification, bar 500 .mu.m). As a comparison, a SEM image of the
particles prepared according to Example 1 of WO 2016/120530 is
shown in FIG. 3 (500 fold magnification, bar 30 .mu.m). The
particles prepared according to the present invention exhibit
rounded particle shape with narrow particle size distribution while
the particles prepared according to WO 2016/120530 are small and
irregular with sharp edges.
Example 6. Determination of Specific Surface Area (SSA) of
Particles
The specific surface area (SSA) and particle size distribution
(PSD) were determined for two batches (A and B) of crystalline
rounded particles of compound (I) prepared according to the present
invention. The particles of the two batches were then milled
followed by the determination of SSA and PSD. The results are shown
in Tables 1 and 2. The results show that the specific surface area
(SSA) of the particles did not significantly change even if the
particles were milled to reduced particle size.
TABLE-US-00001 TABLE 1 Volume Volume Volume particle particle
particle SSA size, Dv10 size, Dv50 size, Dv90 Batch (m.sup.2/g)
(.mu.m) (.mu.m) (.mu.m) A (unmilled) 13 171 407 625 A (milled) 14 2
36 218
TABLE-US-00002 TABLE 2 Volume Volume Volume Specific particle
particle particle surface area size, Dv10 size, Dv50 size, Dv90
Batch (m.sup.2/g) (.mu.m) (.mu.m) (.mu.m) B (unmilled) 12 176 389
826 B (milled) 13 3 96 292
The specific surface area was measured using the three-point
nitrogen adsorption technique based on the Brunauer, Emmett and
Teller (BET) theory using TriStar 3000 automated gas adsorption
analyzer (Micromeritics, Inc.). The samples were vacuum dried for
20 hours in 40.degree. C. The volumetric method was applied at the
relative pressure range 0.1-0.3 P/P.sub.0.
* * * * *